There are dozens of materials used today for the repair and regeneration of bony defects. Bone is composite material that is comprised of collagen, cells, a form of calcium hydroxyapatite crystals and small quantities of other proteins and organic molecules. The chemistry and physical nature of this composite affords it unique properties of high strength, rigidity, and an ability to adapt to changing loads in the body. However, when injuries to bone occur it is sometimes necessary to find a way to fill voids or gaps, and to encourage the repair and regeneration of the bone tissue.
Autograft bone, usually taken from the iliac crest remains the gold standard for filling bony defects. Autograft bone is said to be osteoinductive; that is it will grow bone wherever it is placed in the body due to the cellular content and the presence of growth factors. Despite the generally favorable results from autograft transplants, there remain serious concerns about donor site morbidity, graft collapse and length of hospital stay in comparison to using other materials. Allograft bone in various forms has also been used extensively as bone grafts with mixed results. Allograft, while yielding outcomes generally similar to autograft, is expensive to produce, is generally slower to incorporate, and is variable in performance due to different processing methods and carries the potential risk of infection and disease transmission, though that risk is quite small.
Due to the issues with autograft and allograft bone, a number of other materials, including xenograft and synthetic biomaterials have been used in various bone grafting procedures. Hydroxyapatite bone substitutes have been used somewhat successfully in certain long bone fractures. These materials are said to be osteoconductive. That is, they allow bone to grow along the surface of the material and actually act as a scaffold for new bone growth. This osteoconductive ability depends on the composition, physical structure, porosity and method of manufacture of these materials.
Hydroxyapatite materials have been used mainly in dental procedures and in some long bone grafting procedures. In cervical fusion procedures there have been few reports of the use of synthetic hydroxyapatite. In a clinical study by Zdeblick, coralline-derived HA (ProOsteon, Interpore Cross, Irvine, Calif.) was evaluated in non-instrumented cervical fusion with less than half the grafts incorporating. In that study 14% of grafts extruded and 29% collapsed. Tri calcium phosphates are another form a ceramic material that is used, usually in a porous form for non-load bearing bone grafts. While the success has been good in small defects, the particulate material is somewhat difficult to work with and cannot always be maintained in the surgical site.
Calcium sulfate materials are a form of highly resorbable ceramic bone graft substitute. These have been used with some success as well, but are again limited in their use due to the particulate nature of the material and the difficulty of keeping it in the surgical site. In addition, there have been reports that the material resorbs too quickly, leaving bone voids and poor clinical outcomes. In addition to the synthetic bioceramic materials, there has been some attempt to use xenograft bone for repair and regeneration. However, there is always a risk of antigenicity from this bone, derived mainly from the atelo groups on the collagen fibers within the bone structure. There is also a fear of transmission of CJD (Crutzfeld Jacobs Disease) from the bovine source, although the risk is actually quite small. However, these elements have severely limited its use.
Calcium, sodium phosphosilicate materials, commonly referred to as bioactive glasses are another class of bioceramic material that has been successfully used in bone graft procedures. Calcium sodium phosphosilicates are unique in that they are not only osteoconductive but are also osteostimulative. When exposed to an aqueous environment, such as found in bony defects, the material releases specific ions (Ca, P, Si, Na) in certain concentrations over time. Due to this release of ions, the surface changes and becomes an excellent structure to support cell adhesion, proliferation and differentiation.
Numerous in-vitro and in-vivo studies have shown that these compounds stimulate the rapid proliferation and differentiation of osteoblasts compared with other bone graft materials. In-vitro studies have demonstrated that exposure of osteoblasts to bioactive glass actually upregulates a family of genes that are involved in cellular proliferation as well as differentiation into an osteoblasts phenotype. Additional studies have demonstrated that the ionic extracts released from the bioactive glass particles can actually upregulate primary osteoblasts compared with control samples, accelerating the rate of cell differentiation. Earlier cell culture studies with primary osteoblasts had shown that after 21 days, three-dimensional bone nodules greater than 3 mm in length had formed when cultured on bioactive glass disks. Recent studies have also demonstrated that certain concentrations of the extracts released from bioactive glasses have a pro-angiogenic response. This property would be especially important in the early stages of wound healing and creating an environment favorable for new bone formation. In light of the results with the ionic extracts described and the surface reactive nature of the bioactive glass when exposed to an aqueous environment, those results are consistent with our knowledge of these materials and help to explain the robust bone regenerative properties of this material.
Recently, a clinical study was published comparing bioactive glass (NovaBone, NovaBone Products, LLC) with autograft in adolescent idiopathic scoliosis cases. The average follow-up was 40 months. The results showed a higher complication rate with autograft compared with the bioactive glass (not statistically significant) and a greater loss of correction with autograft compared with the bioactive glass (p=0.025) which was statistically significant. In addition, blood loss was significantly less in the bioactive glass group (1280 mL in the autograft group versus 853 mL in the bioactive glass group). The authors concluded that bioactive glass was effective as a bone graft in these procedures and performed equivalently with autograft. However, in the particulate form, bioactive glass particles are limited by the same constraints as the other bioceramic materials.
In an attempt to improve on the use of particulate materials, there have been a number of composite and putty-like materials that have been developed for bone regeneration. Because calcium phosphate materials are very similar to bone mineral these have been incorporated with many other bioresorbable and non-resorbable polymers. One of the most often cited and used materials in this regard is collagen, because the combination of the calcium phosphate and collagen is close in composition to natural bone. In one example a solid composite is formed by taking collagen from about 5% up to 75% and precipitating a calcium salt and a phosphate containing salt to form a homogeneous composite (U.S. Pat. No. 5,320,844). While this produces a workable material, it is limited by the size and shape because the precipitation of the soluble calcium and phosphate materials will preferentially occur on the surface and the composition of the composite will vary throughout the structure. This would naturally lead to variable properties of the material.
Another variation of this precipitation process is disclosed in U.S. Pat. No. 6,395,036, where a matrix of a bioresorbable polymer (collagen) is exposed to different solutions of calcium ions and phosphate ions such that there is more hydroxyapatite in the body of the composite than on the surface. This is achieved through careful control of pH and concentration of the ionic solutions as well as the order and rate at which they are exposed to the collagen matrix.
The U.S. Pat. No. 6,187,047 describes a process where dilute solutions of collagen, type I, are mixed with fine particles of calcium phosphate, where the particles are 5 microns or less. This process forms a porous 3-dimensional matrix that maintains its structural integrity for at least 3 days and maintains porosity for up to 14 days. While this method allows for the immobilization of the particles initially, once the material starts to degrade, the release of small particles can be problematic is it is know that small particles can cause an osteolytic process that results in inflammation and bone resorption.
U.S. Pat. No. 6,417,166 discloses a thin flexible mineralized collagen membrane for such uses as guided barrier membranes and periodontal defect repair as well as bone grafts and wound repair. The process utilizes up to 70% collagen with 30% to 70% calcium phosphate minerals. The process relies on the addition of calcium solutions and phosphate solutions to a collagen slurry and casting the slurry into a mold and drying said mixture. This is said to form a mineralized collagen composite. This process is severely limited, however, to thin small membranes as the process is ineffective and very expensive for making larger shapes and forms.
Other examples of collagen-calcium phosphate composites can be found in U.S. Pat. No. 6,764,517 and U.S. Pat. No. 6,902,584. In these patents, a 3-dimensional mineralized collagen composite is produced by creating collagen slurry, freezing and lyophilizing the mixture and then subjecting it to calcium and phosphate solutions to form a porous mineralized matrix. These patents further describe adding a soluble collagen in an additional step and lyophilizing that mixture to form the porous composite. The inventions further describe the ability to use various cross-linking agents to enhance physical stability and increased implant resonance time and shape retention. While this technology can produce an improvement over the previous technologies, the manufacturing process consists of many different steps which become costly and very time consuming.
Further refinements of these general methods for producing collagen—calcium phosphate composite materials can be found in U.S. Pat. No. 7,156,880 and U.S. Pat. No. 7,166,133. These inventions describe the manufacture of implants that consist of an osteoconductive matrix that comprises a blend of both insoluble and soluble collagen where at least a portion of the implant is porous. In addition these structures may contain osteoinductive molecules as well as biodegradable synthetic polymers. The patents also describe the incorporation of ceramic materials such as calcium phosphate, calcium sulfate or hydroxyapatite in the form of discrete particles, rather than forming the compounds through precipitation of salts.
More recent technologies, such as those found in U.S. Pat. No. 7,531,004 and U.S. Pat. No. 7,534,451 describe a bone restorative composite material that consists of a resorbable polymer that can be collagen, a range of meso, micro and macro porosity to allow for the inclusion of fluid and to assist in bone ingrowth, as well as the inclusion of calcium phosphate particles. The patents further describe a specific oxidation-reduction reaction of very specific calcium and phosphorous containing salts to precipitate calcium phosphate within the collagen structure. These devices typically require very precise control of the chemistry in order to obtain the desired results of the precipitation of the calcium phosphate materials and appear to be limited to calcium based osteoconductive materials.
While the above referenced composite materials and methods of their delivery are an improvement over the use of particulate materials there is still a need for a cost-effective material that can be widely used in bone regenerative surgery, and that will enhance the bone healing. While calcium phosphate materials are osteoconductive the osteostimulative effects of calcium-sodium phosphosilicate materials such as described above would enhance the robustness of bone healing. Such materials could also carry additional bio-molecules, growth factors or other therapeutic agents. There is also need for improved delivery methods, kits and systems. Therefore, it is an object of this invention to provide a cost effective, easily manufactured bone restorative material that enhances the bone regeneration of damaged osseous tissue, will remain in the surgical site, and gradually resorb over time to leave only natural bone tissue in the regenerated site as well as methods, kits and system for delivery of the bone restorative material.